RU2332408C2 - AMIDE DERIVATIVES OF 2,3,4,5-TETRAHYDROBENZO {f}-{1,4} OXAZEPINE-5-CARBOXYLIC ACID AS INHIBITOR OF Y-SECRETASE FOR TREATMENT OF ALZHEIMER'S DISEASE - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: claim describes benzoxazepinone derivatives of formula

: wherein R¹ represents hydrogen, C₁-C₆ alkoxy, halogen or NR'R", n is 1 or 2, R', R" independently from each other represents hydrogen or C₁-C₆ alkyl; R² represents hydrogen, C₁-C₆ alkyl -(CH₂)_m-C₃-C₇-cycloalkyl, -(CH₂)_m-phenyl or -(CH₂)_m-O-C₁-C₆ alkyl; m is 0.1 or 2; R³ represents C₁-C₆ alkyl,-(CH₂)_m-C(O)O-C₁-C₆ alkyl, C₃-C₇ cycloalkyl or -(CH₂)_m-phenyl which is unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen, trifluoromethyl, -NR'R", nitro and -SO₂NH₂, or represents -C₃-C₇ -cycloalkyl, unsubstituted or substituted by phenyl, or is -(CR′R″)_o-heterocyclyl, selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indol-3-yl optionally substituted by halogen or C₁-C₆ alkoxy group, or thiophen-2-yl, furan-2-yl, NH-pyridin-2-yl optionally substituted by nitro group or benzoimidazol-2-yl, 2-oxo-tetrahydrofuran, and benzo[1,3]dioxol-5-yl and represents -tetrahydro-naphthalen-1-yl, -CHR′-naphthalen-2-yl, -fluoren-9-yl, -(CH₂)_o-S-lower alkyl, -(CH₂)_o-S-benzyl, -(CH₂)_o-C(O)NH₂, -(CH₂)_oNR′R″, -CH[C(O)NH₂]-(CH₂)_o-phenyl, -(CH₂)_o-CF₃, or -(CH₂)_o-CR′R″-CH₂-NR′R″; and o is 1 or 2; or their pharmaceutically suitable acid addition salts, excluding: phenetylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, phenetylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid. The pharmaceutical on basis of the compounds of formula I aimed at the treatment of Alzheimer's disease is described.

EFFECT: production of the new compounds, benzoxazepinone derivatives having useful biological properties.

26 cl, 196 ex

Description

The present invention relates to benzoxazepinone derivatives of the formula

where R ¹ represents hydrogen, lower alkoxy, halogen or —NR′R ″;

n is 1 or 2;

R ′, R ″ independently of each other are hydrogen or lower alkyl;

R ² represents hydrogen, lower alkyl, - (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m- phenyl or- (CH ₂ ) _m -O- (lower alkyl);

m is 0, 1 or 2;

R ³ represents lower alkyl, - (CH ₂ ) _m —C (O) O- (lower alkyl), cycloalkyl or - (CH ₂ ) _m- phenyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen or lower alkyl;

R ⁴ is - (CH ₂ ) _o- phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, —NR′R ″, nitro or —SO ₂ NH ₂ , or

represents cycloalkyl unsubstituted or substituted by phenyl,

or is - (CR'R '') _o- heterocyclyl selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indol-3-yl, optionally substituted with halogen or a lower alkoxy group, or thiophene -2-yl, furan-2-yl, -NH-pyridin-2-yl, optionally substituted with a nitro group,

or benzoimidazol-2-yl, 2-oxotetrahydrofuran, 1-benzylpiperidin-4-yl, or benzo [1,3] dioxol-5-yl,

or is tetrahydronaphthalen-1-yl,

- CHR'-naphthalene-2-yl,

- fluoren-9-yl,

- (CH ₂ ) _o —S-lower alkyl,

- (CH ₂ ) _o- S-benzyl,

- (CH ₂ ) _o —C (O) NH ₂ ,

- (CH ₂ ) _o NR'R '',

- CH [C (O) NH ₂ ] - (CH ₂ ) _o- phenyl,

- (CH ₂ ) _o —CF ₃ ,

- (CH ₂ ) _o -CR'R '' - CH _2- NR'R ''

and o represents 1 or 2,

and their pharmaceutically acceptable acid addition salts (salts, acid addition products), with the exception of the following compounds:

4-benzyl-3-oxo-2,3,4,5-tetrahydrobenzo | f] [1,4] oxazepine-5-carboxylic acid phenethylamide,

4-benzyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide,

4-cyclohexyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid phenethylamide,

4-cyclohexyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide.

These excluded compounds are described, in particular, in J. Org. Chem., 1999, 64, 1074-1076, in connection with a process in which bifunctional starting materials containing functional groups of an aldehyde and a carboxylic acid are used.

As used herein, the term “lower alkyl” means a straight or branched chain saturated alkyl group containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert- butyl and the like. Preferred lower alkyl groups are groups containing 1-4 carbon atoms.

The term "cycloalkyl" means a saturated carbocyclic group containing 3-7 carbon atoms.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "lower alkoxy" means a group in which the alkyl residues are as defined above, and which are attached via an oxygen atom.

The term "pharmaceutically acceptable acid addition salts" means salts with inorganic and organic acids, for example, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid tartaric acid, methanesulfonic acid, n-toluenesulfonic acid and the like.

It has been found that compounds of general formula I are γ-secretase inhibitors and related compounds can be used to treat Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in old age. In terms of pathology, Alzheimer's disease is characterized by deposition in the brain of amyloids, in extracellular plaques and intracellular neurofibrillary nodes. Amyloid plaques are mainly composed of amyloid peptides (Abeta peptides), which arise from the β-amyloid precursor protein (APP - abbr. From the English. Amyloid Precursor Protein) as a result of several stages of proteolytic cleavage. Several forms of APP have been identified, the predominant of which are proteins consisting of 695, 751 and 770 amino acids. They all arise from a single gene through differential splicing. Abeta peptides originate from the same APP domain, but differ in their N- and C-terminus; the main representatives are 40 and 42 amino acids in length.

Abeta peptides are produced from APP through the sequential action of 2 proteolytic enzymes called β- and γ-secretases. β-Secretase exerts a cleavage effect first in the extracellular domain of APP just outside the trans-membrane domain (TM stands for trans-membrane) with the C-terminal fragment of APP produced in this process containing the TM domain and the cytoplasmic domain (CTFβ). CTFβ is a substrate for γ-secretase, which has a cleavage effect in several neighboring positions within the TM domain with the Abeta peptides and cytoplasmic fragment produced. Most of the Abeta peptides have a length corresponding to 40 amino acids (Aβ40), a small amount of such peptides contains an additional 2 amino acids at the C-ends. The latter are supposed to be the most pathogenic amyloid peptides.

β-secretase is a typical aspartyl protease. γ-Secretase has proteolytic activity and consists of several proteins, their exact structure is not fully established. However, presenilins are essential components of the manifestation of such activity and can represent a new group of atypical aspartyl proteases that have a cleavage effect within the TM domains of their substrates and which themselves are polytopic membrane proteins. Other essential components of γ-secretase may be nicastrin and products of the aph1 and pen-2 genes. The confirmed substrates for γ-secretase are APP and proteins of the Notch receptor family, however, γ-secretase has specificity for the loop substrate and can further cleave membrane proteins not belonging to the APP and Notch families.

The activity of γ-secretase is absolutely necessary for the production of Abeta peptides. This has been shown as genetic methods, i.e. ablation of presenilin genes, and inhibition of low molecular weight compounds. Since, according to the amyloid hypothesis of Alzheimer's disease, the production and deposition of Abeta peptides is the main cause of the disease, it is believed that selective and effective γ-secretase inhibitors will be useful for the prevention and treatment of Alzheimer's disease.

Thus, the compounds of the present invention will be useful in treating Alzheimer's disease by blocking the activity of γ-secretase and reducing or preventing the formation of various amyloidogenic Abeta peptides.

The current state of research in the field of inhibition of γ-secretase is the subject of many publications, for example, the following publications:

Nature Reviews / Neuroscience, Vol. 3, April 2002/281,

Biochemical Society Transactions (2002), Vol. 30, part 4,

Current Topics in Medicinal Chemistry, 2002, 2, 371-383,

Current Medicinal Chemistry, 2002, Vol.9, No.11, 1087-1106,

Drug Development Research, 56, 211-227, 2002,

Drug Discovery Today, Vol.6, No.9, May 2001, 459-462,

FEBS Letters, 483, (2000), 6-10,

Science, Vol. 297, 353-356, July 2002, and

Journ. of Medicinal Chemistry, Vol. 44, No.13, 2001, 2039-2060.

The aim of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of drugs for the treatment of diseases associated with inhibition of γ-secretase, the preparation of these compounds, drugs based on the compounds of the present invention and their preparation, as well as the use of compounds of formula I for the control or prevention of Alzheimer's disease.

Another objective of the present invention are all types of optically pure enantiomers, racemates and diastereomeric mixtures of compounds of formula I.

The most preferred compounds are those compounds in which R ² represents lower alkyl.

Particularly preferred are compounds of this group in which R ³ is cycloalkyl and R ⁴ is - (CH ₂ ) _o- phenyl substituted with a dihalo or —NR′R ″ group, or is tetrahydropyran-4-yl, or is tetrahydronaphthalene- 1-yl, or means - (CH ₂ ) _o -pyridin-3-yl.

The following specific compounds belong to this group:

7-bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide,

7-chloro-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide,

7-bromo-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide and

7-bromo-4- (4-dimethylaminobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide, or

7-chloro-2-ethyl-3-oxo-4- (tetrahydropyran-4-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide, or

7-chloro-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid and

8-diethylamino-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid, or

7-chloro-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide.

Other preferred compounds are those in which R ² is lower alkyl, where R ³ is lower alkyl and R ⁴ is - (CH ₂ ) _o- phenyl substituted with a dihalo or NR′R ″ group, or

- (CR'R '') _o indol-3-yl substituted with lower alkoxy, or

cycloalkyl or

- (CH ₂ ) _o- benzo [1,3] dioxol-5-yl, or

- 1-benzylpiperidin-4-yl.

The following specific compounds belong to this group:

7-chloro-4- (2,6-difluorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide,

4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid,

7-chloro-4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid,

4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid,

tert-butylamyl 7-bromo-4- (4-dimethylaminobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid,

9-ethoxy-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1] , 4] oxazepine-5-carboxylic acid,

7-chloro-4-cyclopentyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide,

4-benzo [1,3] dioxol-5-ylmethyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5- tert-butylamide carboxylic acid

4- (1-benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide.

Further preferred are those compounds in which R ² is lower alkyl, where R ³ is - (CH ₂ ) _m -fnil and R ⁴ is cycloalkyl.

The following specific compound belongs to this group:

7-chloro-4-cyclohexyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide.

Further preferred are those compounds in which R ² is lower alkyl, where R ³ is - (CH ₂ ) _m —C (O) O-lower alkyl and R ⁴ is - (CH ₂ ) _o- phenyl substituted CF ₃ group or halogen.

The following specific compounds belong to this group:

{[7-chloro-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ester } acetic acid and

tert-butyl ester {[7-bromo-4- (2-chlorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 -carbonyl] amino} acetic acid.

The compounds of formula I according to the present invention and their pharmaceutically acceptable salts can be obtained using methods known from the prior art, for example in accordance with the methods described below, such methods include:

a) the interaction of the compounds of formula

with a compound of the formula

and with the compound of the formula

with the receipt of the compounds of the formula

and if necessary, converting the resulting compounds into pharmaceutically acceptable salts with acids (salts are acid addition products).

The compounds of formula I can be obtained in accordance with the following scheme 1.

Scheme 1

In this scheme, R ¹ -R ⁴ are as described above.

General synthesis of the skeleton of benzoxazepinones is described in Zhang et al .: J. Org. Chem. 1999, 64, 1074 ff. The corresponding o-hydroxybenzaldehyde (V) is reacted with an alpha-bromocarboxylic acid alkyl ester (VI) to produce an alkyl ester of 2-formylphenoxyacetic acid (VII), which is then saponified to give 2-formylphenoxyacetic acid (II). This acid is reacted with amine (III) and isonitrile (IV) in accordance with a reaction of the Ugi type to obtain a benzoxazepinone derivative of formula I.

The starting compounds (hydroxybenzaldehyde V and α-bromosubstituted esters VI) are commercially available or can be obtained in accordance with known methods.

A detailed description can be found below and in examples 1-196.

Some compounds of formula I can be converted to the corresponding acid addition salts, for example, compounds containing an amino group.

The conversion is carried out by treatment with at least a stoichiometric amount of a suitable acid, for example, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or a stoichiometric amount of an organic acid, for example, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid Ota, citric acid, benzoic acid, cinnamic (β-phenylacrylic acid), mandelic acid, methanesulfonic acid, ethanesulfonic acid, n-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and acid is added in a similar solvent. The temperature is maintained in the range from 0 to 50 ° C. The resulting salt precipitates spontaneously or may be precipitated with a less polar solvent.

The acid addition salts of the compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base, for example, sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula I and their pharmaceutically acceptable addition salts possess valuable pharmacological properties. In particular, it has been found that the compounds of the present invention can inhibit γ-secretase.

Compounds were tested in accordance with the methods below.

Γ-secretase study description

The activity of the tested compounds can be evaluated during the study, according to which the proteolytic cleavage of the corresponding substrates under the action of γ-secretase is quantified. These may be cell studies where, for example, a γ-secretase substrate is fused in its cytoplasmic domain with a transcription factor. Cells are transfected with a fusion gene and a reporter gene, for example, firefly beetle luciferase, using a transcription factor as an enhancing agent for this expression. Cleavage of the fusion substrate by γ-secretase will result in expression of a reporter gene, which can be monitored using appropriate techniques. The activity of γ-secretase can also be established by in vitro analysis without the use of cells, according to which, for example, a cell lysate containing a complex of γ-secretase is incubated with a suitable APP-derived substrate, which is cleaved to form Abeta peptides. The number of produced peptides can be determined by special analysis by ELISA (enzyme-linked immunosorbent assay). Neuronal cell lines secrete Abeta peptides, which can be quantified using a special ELISA. Treatment with compounds that inhibit γ-secretases leads to a decrease in the number of secreted Abeta-pptides, which allows a quantitative assessment of the inhibition.

An in vitro study of the activity of γ-secretase is carried out using the HEK293 membrane fraction as a source of γ-secretase and using a recombinant APP substrate. The latter consists of the C-terminal 100 amino acids of human APP fused to the 6 x histidine tail for purification, and is expressed in E. coli in a regulated expression vector such as pEt15, for example. Such a recombinant protein corresponds to a truncated APP fragment, which is formed after cleavage of the extracellular domain with γ-secretase and which constitutes a γ-secretase substrate. The principles on which the study is based are disclosed in Li Y.M. et al PNAS 97 (11), 6138-6143 (2000). Hek293 cells mechanically destroy and isolate the microsomal fraction by differential centrifugation. Membranes are solubilized in a detergent (0.25% CHAPSO) and incubated with APP substrate. Abeta peptides that are produced by cleavage of the substrate by γ-secretase are recorded using a specific ELISA as described in M. Brockhaus et al., Neuroreport 9 (7), 1481-1486 (1998).

Preferred compounds are characterized by an IC ₅₀ 1,0 1.0 value. The table below shows some characteristics of the inhibition of γ-secretase

Example No. IC ₅₀ in vitro Example No. IC ₅₀ in vitro one 0.28 115 0.97 10 0.97 117 0.89 12 1.05 122 0.96 16 0.89 133 0.31 thirty 1.10 134 0.18 36 0.77 150 0.67 76 1.16 160 0.46 86 0.83 165 0.88 89 1,04 178 0.81 96 0.62 186 0.52

The compounds of formula I and pharmaceutical salts of the compounds of formula I can be used as pharmaceuticals, for example, in the form of pharmaceutical preparations. Pharmaceutical preparations may be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. In addition, the introduction can be effectively carried out rectally, for example, in the form of suppositories, parenterally, for example, in the form of solutions for injection.

The compounds of formula I can be used together with pharmaceutically inert, inorganic or organic carriers to obtain pharmaceutical compositions. As carriers for tablets, coated tablets, dragees and hard gelatine capsules, for example, lactose, corn starch or its derivatives, talc, stearic acids or their salts and the like compounds can be used. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active compound, in the case of soft gelatin capsules, the carrier may not be used. Suitable carriers for solutions and syrups are, for example, water, polyols, glycerin, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wettability agents, emulsifiers, sweeteners, coloring agents, taste and odor improving agents, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically significant compounds.

Medicines containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as well as a process for their preparation, which comprises administering one or more compounds of formula I and / or a pharmaceutically acceptable acid addition salt and, if necessary, one or more therapeutically significant substances in the composition of the drug, together with one or more therapeutically inert carriers.

In accordance with the present invention, the compounds of formula I, as well as their pharmaceutically acceptable salts, can be used to control or prevent diseases, which is based on the inhibition of γ-secretase activity, for example, to control or prevent a disease such as Alzheimer's disease.

Dosage can vary within wide limits and will, of course, be regulated depending on individual requirements in each case. In the case of oral administration, the dosage for adults can range from about 0.01 mg to about 1000 mg per day of a compound of general formula I or an appropriate amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as a single dose or divided into several doses and, in addition to this, the upper limit may be exceeded if it is found that it is necessary according to indications.

Tablet making (wet granulation)

Position Ingredients mg / tablet 5 mg 25 mg 100 mg 500 mg one. The compound of formula I 5 25 one hundred 500 2. Anhydrous Lactose DTG 125 105 thirty 150 3. Sta-Rx 1500 6 6 6 thirty four. Microcrystalline cellulose thirty thirty thirty 150 5. Magnesium stearate one one one one Total amount 167 167 167 831

The method of obtaining

1. Mix the compounds at positions 1, 2, 3 and 4 and carry out granulation using purified water.

2. Dry the granules at 50 ° C.

3. Pass the granules through a suitable milling device.

4. Add the substance according to position 5 and mix for three minutes, then press using a suitable press.

Getting capsules

Position Ingredients mg / capsule 5 mg 25 mg 100 mg 500 mg 1. The compound of formula IA or IB 5 25 one hundred 500 2. Aqueous lactose 159 123 148 - 3. Corn starch 25 35 40 70 4. Talc 10 fifteen 10 25 5. Magnesium stearate one 2 2 5 Total amount 200 200 300 600

Cooking technique

1. Mix the compounds at positions 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add the compounds according to positions 4 and 5 and mix for 3 minutes.

3. Put in suitable capsules

The following examples illustrate the present invention without limiting it. Examples are compounds that can exist as diastereomeric mixtures, racemates, or as optically pure compounds.

Example 1

7-Bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

a) 2- (4-Bromo-2-formylphenoxy) -3-methylbutyric acid

To a solution of 0.67 g (3.3 mmol) of 5-bromosalicylaldehyde in dimethylformamide (6 ml) was added in small portions 0.2 g of sodium hydride (60% suspension in mineral oil, 5 mmol) at 0 ° C. After stirring for approximately half an hour, 1.05 g of 2-bromo-3-methylbutyric acid ethyl ester (5 mmol) was slowly added at room temperature and the resulting mixture was stirred at 90 ° C. overnight. After cooling, ice water (25 ml) and 1N are added. sodium hydroxide solution to alkaline pH of the solution. The resulting mixture was extracted three times with ethyl acetate, the combined organic layers were dried (MgSO ₄ ) and evaporated. After filtration on a short column of the obtained residue, an ester is obtained, which is used in the next step without further purification.

The resulting ester was dissolved in 2 ml of methanol and 2N was added. aqueous sodium hydroxide solution (2 ml). After stirring for 1 hour at room temperature, the solvent was removed on a rotary evaporator. Add water (3 ml) and 4n. hydrochloric acid solution until pH4 is reached. The resulting mixture was extracted three times with ethyl acetate, the combined organic layers were dried (MgSO ₄ ) and evaporated to give 0.125 g of the title compound as a colorless oily substance. Mass spectrum, m / e (%): 299.0 (M-H ⁺ , 93); 301.0 (MH ⁺ , 100).

b) Cyclohexylamide 7-bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

To a solution of 0.12 g of 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid (0.4 mmol) in dimethyl sulfoxide (0.8 ml) was added 0.057 g of 2,6-difluorobenzylamine (0.4 mmol) and 0.044 g of cyclohexyl isocyanide (0.4 mmol) and the resulting mixture was stirred overnight. Then add a 10% aqueous solution of sodium chloride (5 ml), after which the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO ₄ ) and evaporated in vacuo. The resulting residue was purified using column chromatography with ethyl acetate / hexane (1: 4) as the eluent, to give 0.03 g of the title compound as a light yellow foam.

Mass spectrum, m / e (%): 535.3 (M + H ⁺ , 100); 537.3 (M + H ⁺ , 95).

Example 2

7,4-Bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid 3,4-dichlorobenzylamide

The title compound was prepared in a comparable yield according to the procedure described in Example 1, for example, using 1,2-dichloro-4-isocyanomethylbenzene instead of cyclohexyl isocyanide in step b).

Mass spectrum, m / e (%): 629 (M + H ₂ O + H ⁺ , 58); 630 (M + H ₂ O + H ⁺ , 100).

Example 3

7-Bromo-4- (2,6-difluorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

2,6-Difluorobenzylamine (51 mg, 0.35 mmol) and cyclohexyl isocyanide (39 mg, 0.36 mmol) are added to a solution of 2- (4-bromo-2-formylphenoxy) butyric acid (obtained by the same procedure as in Preparation 2 - (4-bromo-2-formylphenoxy) -3-methylbutyric acid [Example 1], from ethyl 2-bromo-3-methylbutyric acid (100 mg, 0.35 mmol) in methanol (0.5 ml). After stirring for 2 hours at room temperature, the title compound (diastereomer 1 [has inhibitory activity], retention time 2.09 min, 17.9 mg; diastereomer 2 [has inhibitory activity], retention time 2.28 min, 7.3 mg, total yield 14%, mass spectrum: m / e = 521.1 [M + H ⁺ ]) was isolated from the reaction mixture by reverse-phase, preparative HPLC (liquid high-resolution chromatography) (YMC CombiPrep C18 column, 50 × 20 mm, solvent — gradient of 5-95% CH ₂ CN in 0.1% TFA (aq) for 6.0 min, λ = 230 nm, flow rate 40 ml / min.).

Example 4

7-Bromo-2-cyclohexylmethyl-4- (2,6-difluorobenzyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 589.4 [M + H ⁺ ], was prepared according to the procedure similar to that described in Example 3, from 2- (4-bromo-2-formylphenoxy) -3-cyclohexylpropionic acid (obtained by a method similar to the method of obtaining 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-3-cyclohexylpropionic acid) as a mixture of diastereomers.

Example 5

7-Bromo-2-butyl-4- (2,6-difluorobenzyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 549.4 [M + H ⁺ ], was prepared according to the procedure similar to that described in Example 3, from 2- (4-bromo-2-formylphenoxy) hexanoic acid (obtained from a procedure similar to the method of obtaining 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from methyl (2-bromocaproate) as a mixture of diastereomers.

Example 6

7-Chloro-4-cyclohexyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 433.5 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine and 2- (4-chloro-2-formylphenoxy) butyric acid ( obtained by a method similar to the method of obtaining 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-n-butyrate and 5-chlorosalicylaldehyde) in the form of two separable diastereomers (both possess inhibitory activity).

Example 7

7-chloro-4- (2-chlorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 475.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine and 2- (4-chloro-2-formylphenoxy) oily acid (obtained by a method similar to the method of obtaining 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-n-butyrate and 5-chlorosalicylaldehyde) as two separable diastereomers (both have inhibitory activity).

Example 8

7-chloro-4-cyclobutyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 405.4 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from cyclobutylamine and 2- (4-chloro-2-formylphenoxy) butyric acid ( obtained by a method similar to that of 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [Example 1], from ethyl 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde) as a mixture of diastereomers.

Example 9

7-Chloro-4-cyclopentyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 419.4 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from cyclopentylamine and 2- (4-chloro-2-formylphenoxy) butyric acid ( obtained by a method similar to the method of obtaining 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl ester of 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde) in the form of two separable diastereomers ( both have inhibitory activity).

Example 10

7-Chloro-2-ethyl-3-oxo-4- (tetrahydropyran-4-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 435.4 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 4-aminotetrahydropyran and 2- (4-chloro-2-formylphenoxy) oily acids (obtained by a method similar to that of 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) as two separable diastereomers (both have inhibitory activity).

Example 11

7-Chloro-2-ethyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum: m / e = 509.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 3-trifluorobenzylamine and 2- (4-chloro-2-formylphenoxy) oily acids (obtained by a method similar to that of 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) as two separable diastereomers (both have inhibitory activity).

Example 12

7-chloro-4- (2,6-difluorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 451.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 2,6-difluorobenzylamine, tert-butylisocyanide and 2- (4-chloro -2-formylphenoxy) butyric acid (obtained by a method similar to the procedure for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-n-butyric acid and 5- chlorosalicylaldehyde) in the form of two separable diastereomers (both have inhibitory activity).

Example 13

7-chloro-4-cyclohexyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 407.4 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, tert-butyl isocyanide and 2- (4-chloro-2-formylphenoxy ) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) in the form two shared diastereomers (both have inhibitory activity).

Example 14

7-chloro-4- (2-chlorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 449.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 2-chlorobenzylamine, tert-butylisocyanide and 2- (4-chloro-2 -formylphenoxy) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde) in the form of two separable diastereomers (both have inhibitory activity).

Example 15

7-chloro-4-cyclobutyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 379.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from cyclobutylamine, tert-butylisocyanide and 2- (4-chloro-2-formylphenoxy ) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde).

Example 16

7-chloro-4-cyclopentyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 393.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from cyclopentylamine, tert-butylisocyanide and 2- (4-chloro-2-formylphenoxy) butyric acid (obtained by a method similar to that of 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1], from ethyl 2-bromo-n-butyrate and 5-chlorosalicylaldehyde) as two separable diastereomers (both have inhibitory activity).

Example 17

7-chloro-2-ethyl-3-oxo-4- (tetrahydropyran-4-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 409.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 4-aminotetrahydropyran, tert-butylisocyanide and 2- (4-chloro-2 -formylphenoxy) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl ester of 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde).

Example 18

7-chloro-2-ethyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum: m / e = 483.5 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 3-trifluoromethylbenzylamine, tert-butylisocyanide and 2- (4-chloro-2 -formylphenoxy) butyric acid (obtained by a method similar to the procedure for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde) in as a mixture of diastereomers.

Example 19

{[7-chloro-4- (2,6-difluorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl tert-butyl ester ] amino} acetic acid

The title compound, mass spectrum: m / e = 509.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from 2,6-difluorobenzylamine, isocyanoacetic acid tert-butyl ester and 2- ( 4-chloro-2-formylphenoxy) butyric acid (obtained by a procedure analogous to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl 2-bromo-n-butyric acid and 5-chlorosalicylaldehyde).

Example 20

[(7-Chloro-4-cyclohexyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl) amino] acetic acid tert-butyl ester

The title compound, mass spectrum: m / e = 465.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, isocyanoacetic acid tert-butyl ester and 2- (4-chloro- 2-formylphenoxy) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) in the form of a mixture of diastereomers.

Example 21

[(7-Chloro-4-cyclobutyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl) amino] acetic acid tert-butyl ester

The title compound, mass spectrum: m / e = 437.3 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from cyclobutylamine, isocyanoacetic acid tert-butyl ester and 2- (4-chloro- 2-formylphenoxy) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) in the form of a mixture of diastereomers.

Example 22

[(7-Chloro-4-cyclopentyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl) amino] acetic acid tert-butyl ester

The title compound, mass spectrum: m / e = 451.4 (M + H ⁺ ), was prepared according to the procedure similar to that described in Example 3 from cyclopentylamine, isocyanoacetic acid tert-butyl ester and 2- (4-chloro- 2-formylphenoxy) butyric acid (obtained by a method similar to the method for producing 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid [example 1] from ethyl 2-bromo-butyric acid and 5-chlorosalicylaldehyde) .

Example 23

7-Chloro-4- (2,6-difluorobenzyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 449.14 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, (4-chloro-2-formylphenoxy) acetic acid. and isocyanocyclohexane.

Example 24

4- (2,6-difluorobenzyl) -6,8-dimethoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 449.18 (M + 1), was prepared according to the procedure similar to that described in Example 3 from 2,6-difluorobenzylamine, (2-formyl-3,5-dimethoxyphenoxy) acetic acid and 2-isocyano-2-methylpropane.

Example 25

6,8-Dimethoxy-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5- cyclohexylamide carboxylic acid

The title compound, mass spectrum, m / e: 479.25 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, (2- formyl-3,5-dimethoxyphenoxy) acetic acid and isocyanocyclohexane.

Example 26

7-Chloro-4- (4-chloro-2-fluorobenzyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 465.1 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, (4-chloro-2-formylphenoxy) acetic acid and isocyanocyclohexane.

Example 27

4- (2,6-difluorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 461.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 28

2-Isopropyl-8-methoxy-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 493.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 29

4- [2- (5-Fluoro-1H-indol-3-yl) -1-methylethyl] -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f ] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 510.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-fluoro-1H-indol-3-yl) -1 -methylethylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 30

4- (4-Dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 438.3 (M + 1), was prepared according to the procedure similar to that described in Example 3 from 4-dimethylaminobenzylamine, 2- (2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 31

2-Isopropyl-4- [2- (5-nitropyridin-2-ylamino) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 496.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-nitropyridin-2-ylamino) ethylamine, 2- (2 -formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 32

7-bromo-4- (9H-fluoren-9-yl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 505.1 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 9H-fluoren-9-ylamine, (4-bromo-2-formylphenoxy) acetic acid and 2-isocyano-2-methylpropane.

Example 33

8-diethylamino-4- (9H-fluoren-9-yl) -2-methyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 512.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 9H-fluoren-9-ylamine, 2- (5-diethylamino-2- formylphenoxy) propionic acid and 2-isocyano-2-methylpropane.

Example 34

7-chloro-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 465.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 35

7-chloro-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 491.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 36

7-Chloro-4- (4-dimethylaminobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 472.2 (M + 1), was obtained by the procedure similar to that described in Example 3 from 4-dimethylaminobenzylamine, 2- (4-chloro-2-formylphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 37

7-Chloro-2-isopropyl-4- (2-methylsulfanylethyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 439.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-methylsulfanyl-ethylamine, 2- (4-chloro-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 38

7-chloro-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide -5-carboxylic acid

The title compound, mass spectrum, m / e: 482.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 -chloro-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 39

7,9-Dichloro-4- (2,6-difluorobenzyl) -2-methyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 497.11 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (2,4-dichloro-6- formylphenoxy) propionic acid and isocyanocyclohexane.

Example 40

tert-Butylamide, 7-bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 509.12 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 41

7-Bromo-4- (2-chlorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 533.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 42

4- (4-Chloro-2-fluorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 552.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (5-diethylamino-2- formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 43

7-Bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 509.1 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 44

7-bromo-4-cyclohexyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 487.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, 2- (4-bromo-2-formylphenoxy) -3-methyl-oil acids and 2-isocyano-2-methylpropane.

Example 45

7-Bromo-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 567.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 46

4- (1-Benzylpiperidin-4-yl) -7-bromo-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 556.21 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 47

tert-Butylamide 7,9-dichloro-2-methyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1, 4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 497.15 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 2,4-dichloro-6-formylphenoxy) propionic acid and 2-isocyano-2-methylpropane.

Example 48

7-bromo-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 535.17 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 4-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 49

7-Bromo-4- (1-carbamoyl-2-phenylethyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 556.17 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-amino-3-phenylpropionamide, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 50

Butylamide 7-bromo-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- 5-carboxylic acid

The title compound, mass spectrum, m / e: 535.17 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 4-bromo-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 51

7-bromo-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 474.13 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 52

7-Bromo-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 500.15 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 53

7-Bromo-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 474.13 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 54

7-bromo-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide -5-carboxylic acid

The title compound, mass spectrum, m / e: 526.16 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 β-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 55

7-Bromo-2-isopropyl-3-oxo-4- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 491.11 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,2,2-trifluoroethylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 56

Butylamide 7-bromo-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 carboxylic acid

The title compound, mass spectrum, m / e: 526.16 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 β-bromo-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 57

7-bromo-4- [2- (5-fluoro-1H-indol-3-yl) -1-methylethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f ] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 580.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2- (5-fluoro-1H-indol-3-yl) -1 -methylethylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 58

4-cyclohexyl-2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 417.27 (M + 1), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric. acids and 2-isocyano-2-methylpropane.

Example 59

4- (3,5-Dichlorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 541.17 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 3,5-dichlorobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 60

4- (2-Chlorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 485.22 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 61

4- (2,6-difluorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 487.23 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 62

2-Isopropyl-8-methoxy-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 493.22 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 63

4- (1-Benzylpiperidin-4-yl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 508.31 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 64

4- (1-Benzylpiperidin-4-yl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 534.33 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 65

4- (1-Benzylpiperidin-4-yl) butylamide -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 508.31 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 66

2-Isopropyl-8-methoxy-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 487.27 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 67

2-Isopropyl-8-methoxy-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid

The title compound, mass spectrum, m / e: 513.28 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 68

2-Isopropyl-8-methoxy-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine butylamide 5-carboxylic acid

The title compound, mass spectrum, m / e: 465.27 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 69

2-Isopropyl-8-methoxy-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 426.23 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 70

4-benzo [1,3] dioxol-5-ylmethyl-2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5- tert-butylamide carboxylic acid

The title compound, mass spectrum, m / e: 469.23 (M + 1), was prepared according to the procedure similar to that described in Example 3, from benzo [1,3] dioxol-5-ylmethylamine, 2- (2- formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 71

2-Isopropyl-8-methoxy-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 452.25 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (2-formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 72

4-Benzo [1,3] dioxol-5-ylmethyl-2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 495.24 (M + 1), was prepared according to the procedure similar to that described in Example 3, from benzo [1,3] dioxol-5-ylmethylamine, 2- (2- formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 73

4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide -5-carboxylic acid

The title compound, mass spectrum, m / e: 478.26 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -formyl-5-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 74

4-Cyclohexylamide [2- (1H-indol-3-yl) ethyl] -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5 carboxylic acid

The title compound, mass spectrum, m / e: 504.28 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -formyl-5-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 75

4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 457.22 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (2-formylphenoxy) -3-methylbutyric. acids and isocyanocyclohexane.

Example 76

4- (1-Benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 478.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 77

4- (1-Benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 504.32 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 78

2-Isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 396.22 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (2-formylphenoxy) -3-methylbutyric. acids and 2-isocyano-2-methylpropane.

Example 79

2-Isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 422.24 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (2-formylphenoxy) -3-methylbutyric. acids and isocyanocyclohexane.

Example 80

4- (3-Dimethylamino-2,2-dimethylpropyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 444.32 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,2, N ', N'-tetramethylpropane-1,3-diamine. , 2- (2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 81

4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic tert-butylamide acid

The title compound, mass spectrum, m / e: 448.25 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 82

4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 448.25 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 83

2-Isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide -5-carboxylic acid

The title compound, mass spectrum, m / e: 478.26 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 84

2-Isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 cyclohexylamide carboxylic acid

The title compound, mass spectrum, m / e: 504.28 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 85

7-Chloro-4- (2-chlorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 489.16 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (4-chloro-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 86

Cyclohexylamide 7-chloro-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- 5-carboxylic acid

The title compound, mass spectrum, m / e: 517.3943 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 87

4- (2-Benzylsulfanylethyl) -7-chloro-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 537.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2-benzylsulfanylethylamine, 2- (4-chloro-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 88

7-chloro-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 430.18 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 89

7-Chloro-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 456.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 90

7-chloro-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 430.18 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 91

7-Chloro-4- (3-diethylaminopropyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 478.28 (M + 1), was prepared according to the procedure similar to that described in Example 3, from N ', N'-diethylpropane-1,3-diamine, 2- ( 4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 93

7-Chloro-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] cyclohexylamide [1,4] ] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 538.24 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 93

4- (4-Chloro-2-fluorobenzyl) -7-methoxy-3-oxo-2-phenyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 511.17 (M + 1), was prepared according to the procedure similar to that described in Example 3 from 4-chloro-2-fluorobenzylamine, (2-formyl-4-methoxyphenoxy) phenylacetic acid and 2-isocyano-2-methylpropane.

Example 94

Butylamide 7-chloro-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 carboxylic acid

The title compound, mass spectrum, m / e: 482.21 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 -chloro-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 95

7-chloro-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1 , 4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 512.22 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 96

7-Chloro-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 507.15 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (4-chloro-2- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 97

7,9-Dichloro-4- (4-chloro-2-fluorobenzyl) -2-methyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 513.08 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (2,4-dichloro- 6-formylphenoxy) propionic acid and isocyanocyclohexane.

Example 98

4- (9H-fluoren-9-yl) -7-methoxy-2-methyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 497.24 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 9H-fluoren-9-ylamine, 2- (2-formyl-4- methoxyphenoxy) propionic acid and isocyanocyclohexane.

Example 99

4- (3,5-Dichlorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 534.22 (M + 1), was prepared according to the procedure similar to that described in Example 3 from 3,5-dichlorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 100

4- (3,5-Dichlorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 560.24 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3,5-dichlorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 101

8-Diethylamino-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 560.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 102

8-Diethylamino-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 cyclohexylamide carboxylic acid

The title compound, mass spectrum, m / e: 545.34 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (5 diethylamino-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 103

4- (4-Dimethylaminobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 494.29 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 104

4- (2-Chlorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 500.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 105

8-diethylamino-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 502.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 106

4- (2-Chlorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 526.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 107

8-Diethylamino-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 528.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 108

4- (2-Chlorobenzyl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 500.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 109

8-diethylamino-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 502.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 110

4-cyclohexyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 458.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric. acids and 2-isocyano-2-methylpropane.

Example 111

8-diethylamino-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 534.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 methylbutyric acid and 2-isocyano-2-methylpropane.

Example 112

8-diethylamino-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 534.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-trifluoromethylbenzylamine, 2- (5-diethylamino-2-formylphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 113

4- (1-Benzylpiperidin-4-yl) -8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo | f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 549.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (5-diethylamino-2- formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 114

8-diethylamino-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 506.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 115

8-Diethylamino-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid

The title compound, mass spectrum, m / e: 532.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 116

Butylamide 8-diethylamino-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- 5-carboxylic acid

The title compound, mass spectrum, m / e: 506.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 117

4-benzo [1,3] dioxol-5-ylmethyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5- tert-butylamide carboxylic acid

The title compound, mass spectrum, m / e: 510.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from benzo [1,3] dioxol-5-ylmethylamine, 2- (5- diethylamino-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 118

4-Benzo [1,3] dioxol-5-ylmethyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 536.4 (M + 1), was prepared according to the procedure similar to that described in Example 3 from benzo [1,3] dioxol-5-ylmethylamine, 2- (5- diethylamino-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 119

4-Benzo [1,3] dioxol-5-ylmethyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 510.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from benzo [1,3] dioxol-5-ylmethylamine, 2- (5- diethylamino-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 120

8-diethylamino-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide -5-carboxylic acid

The title compound, mass spectrum, m / e: 519.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (5 diethylamino-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 121

8-diethylamino-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo butylamide [f] [1,4 ] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 549.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (5-diethylamino-2-formylphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 122

4- (4-Dimethylaminobenzyl) butylamide-2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 468.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-formyl-5-methoxyphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 123

4- (4-Chloro-2-fluorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 477.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 124

4- (4-Chloro-2-fluorobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 503.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 125

4- (4-Chloro-2-fluorobenzyl) butylamide-2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide

The title compound, mass spectrum, m / e: 477.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 126

7-Bromo-4- (2,6-difluorobenzyl) -2-methyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 529.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-bromo-2-formylphenoxy) propionic acid and isocyanocyclohexane.

Example 127

{[4- (1-Benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ester } acetic acid

The title compound, mass spectrum, m / e: 536.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 128

tert-butyl ether ({7-chloro-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f ] [1,4] oxazepine-5-carbonyl} amino) acetic acid

The title compound, mass spectrum, m / e: 592.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 129

({7-chloro-2-isopropyl-4- [2- (4-nitrophenyl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- tert-butyl ether 5-carbonyl} amino) acetic acid

The title compound, mass spectrum, m / e: 546.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-nitrophenylethylamine, 2- (4-chloro-2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 130

4- (1H-Benzoimidazol-2-ylmethyl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 479.3 (M + 1), was prepared according to the procedure similar to that described in Example 3 from benzoimidazol-2-ylmethylamine, 2- (2-ethoxy-6-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 131

4- (1H-Benzoimidazol-2-ylmethyl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 505.3 (M + 1), was prepared according to the procedure similar to that described in Example 3 from benzoimidazol-2-ylmethylamine, 2- (2-ethoxy-6-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 132

7-chloro-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 499.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 133

7-chloro-4-cyclohexyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 455.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, 2- (4-chloro-2-formylphenoxy) -3-methyl-oil acids and isocyanomethylbenzene.

Example 134

{[7-chloro-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ether } acetic acid

The title compound, mass spectrum, m / e: 577.18 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 3-trifluoromethylbenzylamine, 2- (4-chloro-2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 135

4- (1-Benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 512.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-formylphenoxy) -3 -methylbutyric acid and isocyanomethylbenzene.

Example 136

4- (1-Benzylpiperidin-4-yl) -7-chloro-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 546.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-chloro-2- formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 137

{[4- (1-Benzylpiperidin-4-yl) -7-chloro-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 tert-butyl ester -carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 570.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-chloro-2- formylphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 138

{[4- (1-carbamoyl-2-phenylethyl) -7-chloro-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 tert-butyl ester -carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 566.21 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2-amino-3-phenylpropionamide, 2- (4-chloro-2- formylphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 139

7-chloro-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5 benzylamide carboxylic acid

The title compound, mass spectrum, m / e: 516.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 -chloro-2-formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 140

7-chloro-4- (4-dimethylaminobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 528.3 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 4-dimethylaminobenzylamine, 2- (4-chloro-2-formylphenoxy) -3 -methylbutyric acid and isocyanomethylbenzene.

Example 141

{[4- (2-Benzylsulfanylethyl) -7-chloro-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ester } acetic acid

The title compound, mass spectrum, m / e: 569.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2-benzylsulfanylethylamine, 2- (4-chloro-2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 142

{[7-Chloro-2-isopropyl-4- (2-methylsulfanylethyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ester } acetic acid

The title compound, mass spectrum, m / e: 493.3 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 2-methylsulfanylethylamine, 2- (4-chloro-2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 143

{[7-chloro-2-isopropyl-3-oxo-4- (4-sulfamoylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ether } acetic acid

The title compound, mass spectrum, m / e: 588.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 4-aminomethylbenzenesulfonamide, 2- (4-chloro-2-formylphenoxy) -3 methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 144

({2-Isopropyl-4- [2- (5-nitropyridin-2-ylamino) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- tert-butyl ether 5-carbonyl} amino) acetic acid

The title compound, mass spectrum, m / e: 528.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-nitropyridin-2-ylamino) ethylamine, 2- (2 -formylphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 145

4- (2,6-difluorobenzyl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 501.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (2-ethoxy-6-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 146

4- (4-Dimethylaminobenzyl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 482.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-ethoxy-6-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 147

4- (1-Benzylpiperidin-4-yl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 548.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (2-ethoxy-6- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 148

4- (4-Dimethylaminobenzyl) -9-ethoxy-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 529.4 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-ethoxy-6-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 149

9-Ethoxy-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 cyclohexylamide carboxylic acid

The title compound, mass spectrum, m / e: 518.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -ethoxy-6-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 150

9-ethoxy-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1 , 4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 522.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (2-ethoxy-6-formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 151

9-Ethoxy-2-isopropyl-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] cyclohexylamide [1,4] ] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 548.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (2-ethoxy-6-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 152

(2,6-Dimethylphenyl) amide 7-bromo-4- (2-chlorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbon acid

The title compound, mass spectrum, m / e: 555.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 153

(2,6-Dimethylphenyl) amide 7-bromo-4-cyclohexyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 513.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from cyclohexylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric. acids and 2-isocyano-1,3-dimethylbenzene.

Example 154

(2,6-Dimethylphenyl) amide 7-bromo-2-isopropyl-3-oxo-4- (2-thiophen-2-yl-ethyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine -5-carboxylic acid

The title compound, mass spectrum, m / e: 541.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-thiophen-2-yl-ethylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 155

(2,6-Dimethylphenyl) amide 4- (1-benzylpiperidin-4-yl) -7-bromo-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine -5-carboxylic acid

The title compound, mass spectrum, m / e: 604.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 156

(2,6-Dimethylphenyl) amide 7-bromo-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbon acid

The title compound, mass spectrum, m / e: 522.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-bromo-2-formylphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 157

7-bromo-4-carbamoylmethyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide

The title compound, mass spectrum, m / e: 440.2 (M + 1), was prepared according to the procedure similar to that described in Example 3 from 2-aminoacetamide, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 158

7-bromo-4-furan-2-ylmethyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f) [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 485.1 (M + 23), was prepared according to the procedure similar to that described in Example 3, from C-furan-2-ylmethylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 159

7-Bromo-2-isopropyl-3-oxo-4- (2-phenylcyclopropyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 525.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-phenylcyclopropylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 160

7-bromo-4- (4-dimethylaminobenzyl) tert-butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 538.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and 2-isocyano-2-methylpropane.

Example 161

7-Bromo-4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 516.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and 1-isocyanobutane.

Example 162

4- (2-Benzylsulfanylethyl) -7-bromo-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 559.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-benzylsulfanylethylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 163

7-Bromo-2-isopropyl-4- (2-methylsulfanylethyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 483.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-methylsulfanylethylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 164

7-Bromo-2-isopropyl-4- [2- (4-nitrophenyl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 558.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-nitrophenylethylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 165

7-Bromo-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 551.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 166

7-Bromo-4- (4-dimethylaminobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 564.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (4-bromo-2-formylphenoxy) -3 -methylbutyric acid and isocyanocyclohexane.

Example 167

7-Bromo-2-isopropyl-3-oxo-4- (2-oxotetrahydrofuran-3-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 493.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 3-aminodihydrofuran-2-one, 2- (4-bromo-2- formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 168

7-Bromo-2-isopropyl-4- [2- (5-nitropyridin-2-ylamino) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 cyclohexylamide carboxylic acid

The title compound, mass spectrum, m / e: 574.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-nitropyridin-2-ylamino) ethylamine, 2- (4 β-bromo-2-formylphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 169

tert-Butyl ether {[7-bromo-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4 ] oxazepine-5-carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 635.1 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 4-chloro-2-fluorobenzylamine, 2- (4-bromo-2- formyl-6-methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 170

(2,6-Dimethylphenyl) amide 7-bromo-2-isopropyl-9-methoxy-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4 , 5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 634.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 171

(2,6-Dimethylphenyl) amide 7-bromo-2-isopropyl-9-methoxy-4- [2- (5-nitropyridin-2-ylamino) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 626.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-nitropyridin-2-ylamino) ethylamine, 2- (4 bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 172

4- (4-Dimethylaminobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 502.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-formyl-4-methoxyphenoxy) -3 -methylbutyric acid and isocyanomethylbenzene.

Example 173

4- (4-Dimethylaminobenzyl) -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid (2,6-dimethylphenyl) amide acid

The title compound, mass spectrum, m / e: 515.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 4-dimethylaminobenzylamine, 2- (2-formyl-4-methoxyphenoxy) -3 -methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 174

2-tert-butoxymethyl-7-chloro-4- (2,6-difluorobenzyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 557.21 (M + 23), was prepared by the same procedure as in Example 3 from 2,6-difluorobenzylamine, 3-tert-butoxy-2- (4- chloro-2-formylphenoxy) propionic acid and isocyanocyclohexane.

Example 175

2-tert-butoxymethyl-7-chloro-4-furan-2-ylmethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 511.2 (M + 23), was prepared according to the procedure similar to that described in Example 3 from furan-2-ylmethylamine, 3-tert-butoxy-2- (4- chloro-2-formylphenoxy) propionic acid and isocyanocyclohexane.

Example 176

7-Bromo-4- (2,6-difluorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 565.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2,6-difluorobenzylamine, 2- (4-bromo-2-formyl- 6-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 177

4- (1-Benzylpiperidin-4-yl) -7-bromo-2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butylamide 5-carboxylic acid

The title compound, mass spectrum, m / e: 586.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-bromo-2- formyl-6-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 178

7-Bromo-4- (4-dimethylaminobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 594.3 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 4-dimethylaminobenzylamine, 2- (4-bromo-2-formyl-6- methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 179

Butylamide 4- (1-benzylpiperidin-4-yl) -7-bromo-2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5- carboxylic acid

The title compound, mass spectrum, m / e: 586.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-benzylpiperidin-4-ylamine, 2- (4-bromo-2- formyl-6-methoxyphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 180

7-Bromo-4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 568.3 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 4-dimethylaminobenzylamine, 2- (4-bromo-2-formyl-6- methoxyphenoxy) -3-methylbutyric acid and 1-isocyanobutane.

Example 181

7-Bromo-2-isopropyl-9-methoxy-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide

The title compound, mass spectrum, m / e: 530.3 (M + 1), was prepared according to the procedure similar to that described in Example 3 from pyridin-3-ylmethylamine, 2- (4-bromo-2-formyl- 6-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 182

7-bromo-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [f] [1 , 4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 556.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (4 bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 183

7-bromo-2-isopropyl-9-methoxy-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo tert-butylamide [ f] [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 586.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-2-methylpropane.

Example 184

7-Bromo-2-isopropyl-9-methoxy-4- [2- (5-methoxy-1H-indol-3-yl) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] cyclohexylamide [1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 612.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-methoxy-1H-indol-3-yl) ethylamine, 2- (4-bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 185

7-Bromo-2-isopropyl-9-methoxy-4- [2- (5-nitropyridin-2-ylamino) ethyl] -3-oxo-2,3,4,5-tetrahydrobenzo [f] cyclohexylamide [1,4] ] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 604.3 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (5-nitropyridin-2-ylamino) ethylamine, 2- (4 bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and isocyanocyclohexane.

Example 186

tert-Butyl ether {[7-bromo-4- (2-chlorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 -carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 617.2 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 2-chlorobenzylamine, 2- (4-bromo-2-formyl-6- methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 187

[(7-Bromo-4-carbamoylmethyl-2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl) amino tert-butyl ester ] acetic acid

The title compound, mass spectrum, m / e: 550.2 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 2-aminoacetamide, 2- (4-bromo-2-formyl-6- methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 188

{[7-Bromo-4- (3,5-dichlorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine tert-butyl ester -5-carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 651.07 (M + 23), was prepared according to the procedure similar to that described in Example 3 from 3,5-dichlorobenzylamine, 2- (4-bromo-2-formyl- 6-methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 189

tert-Butyl ether {[7-bromo-2-isopropyl-9-methoxy-3-oxo-4- (2-phenylcyclopropyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 -carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 587.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2-phenylcyclopropylamine, 2- (4-bromo-2-formyl-6- methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 190

{[7-Bromo-2-isopropyl-9-methoxy-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo tert-butyl ether [ f] [1,4] oxazepine-5-carbonyl] amino} acetic acid

The title compound, mass spectrum, m / e: 623.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1,2,3,4-tetrahydronaphthalen-1-ylamine, 2- ( 4-bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 191

[(7-Bromo-2-isopropyl-9-methoxy-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 tert-butyl ester -carbonyl) amino] acetic acid

The title compound, mass spectrum, m / e: 562.2 (M + 1), was prepared according to the procedure similar to that described in Example 3, from pyridin-3-ylmethylamine, 2- (4-bromo-2-formyl- 6-methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 192

[(4-Benzo [1,3] dioxol-5-ylmethyl-7-bromo-2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo tert-butyl ester [f] [1 , 4] oxazepine-5-carbonyl) amino] acetic acid

The title compound, mass spectrum, m / e: 627.3 (M + 23), was prepared according to the procedure similar to that described in Example 3 from benzo [1,3] dioxol-5-ylmethylamine, 2- (4- bromo-2-formyl-6-methoxyphenoxy) -3-methylbutyric acid and isocyanoacetic acid tert-butyl ester.

Example 193

(2,6-Dimethylphenyl) amide 9-ethoxy-4- [2- (1H-indol-3-yl) ethyl] -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [ 1,4] oxazepine-5-carboxylic acid

The title compound, mass spectrum, m / e: 540.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 2- (1H-indol-3-yl) ethylamine, 2- (2 -ethoxy-6-formylphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Example 194

8-Diethylamino-2-isopropyl-4- (1-naphthalen-1-yl-ethyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 564.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from 1-naphthalen-1-yl-ethylamine, 2- (5-diethylamino-2- formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 195

8-diethylamino-4-furan-2-ylmethyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide

The title compound, mass spectrum, m / e: 490.4 (M + 1), was prepared according to the procedure similar to that described in Example 3, from C-furan-2-ylmethylamine, 2- (5-diethylamino-2- formylphenoxy) -3-methylbutyric acid and isocyanomethylbenzene.

Example 196

(2,6-Dimethylphenyl) amide 2-isopropyl-8-methoxy-4- (1-naphthalen-1-yl-ethyl) -3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine -5-carboxylic acid

The title compound, mass spectrum: m / e: 559.3 (M + 23), was prepared according to the procedure similar to that described in Example 3, from 1-naphthalen-1-yl-ethylamine, 2- (2-formyl-5- methoxyphenoxy) -3-methylbutyric acid and 2-isocyano-1,3-dimethylbenzene.

Claims (27)

1. Compounds of the general formula

where R ¹ represents hydrogen, C ₁ -C ₆ alkoxy, halogen or -NR'R "'; n is 1 or 2; R ′, R ″ independently of each other are hydrogen or C ₁ -C ₆ alkyl; R ² represents hydrogen, C ₁ -C ₆ alkyl, - (CH ₂ ) _m -C ₃ -C ₇ cycloalkyl, - (CH ₂ ) _m- phenyl or - (CH ₂ ) _m -OC ₁ -C ₆ alkyl ; m is 0, 1 or 2; R ³ is C ₁ -C ₆ alkyl, - (CH ₂ ) _m -C (O) OC ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or - (CH ₂ ) _m- phenyl, which is unsubstituted or substituted one or two substituents selected from the group consisting of halogen or C ₁ -C ₆ alkyl; R ⁴ is - (CH ₂ ) _o- phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, trifluoromethyl, —NR′R ″, nitro or —SO ₂ NH ₂ , or represents —C ₃ -C ₇ cycloalkyl unsubstituted or substituted with phenyl, or represents - (CR′R ″) _o- heterocyclyl selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indole -3-yl, optionally substituted by halogen or a group C ₁ -C ₆ alkoxy, or thiophen-2-yl, furan-2-yl, -NH-pyridin-2-yl, optionally substituted with r uppoy nitro, or benzoimidazol-2-yl, 2-oxo-tetrahydrofuran, 1-benzyl-piperidin-4-yl, or benzo [1,3] dioxol-5-yl, or is tetrahydronaphthalen-1-yl, CHR'-naphthalene -2-yl, fluoren-9-yl, (CH ₂ ) _o -S-lower alkyl, (CH ₂ ) _o -S-benzyl, (CH ₂ ) _o -C (O) NH ₂ , (CH ₂ ) _o NR'R '', CH [C (O) NH ₂ ] - (CH ₂ ) _o- phenyl, (CH ₂ ) _o -CF ₃ , (CH ₂ ) _o -CR'R '' - CH ₂ -NR ' R ''; o means 1 or 2; and their pharmaceutically acceptable acid addition salts, with the exception of the following compounds: 4-benzyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid phenethylamide, 4-benzyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide, 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] -oxazepine-5-carboxylic acid phenethylamide, 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid butylamide. 2. The compound according to claim 1, where R ² represents a C ₁ -C ₆ alkyl. 3. The compound of claim 2, wherein R ³ is C ₃ -C ₇ cycloalkyl and R ⁴ is - (CH ₂ ) _o- phenyl substituted with a dihalo or NR′R ″ group. 4. The compounds according to claim 3, which are the following compounds: 7-bromo-4- (2,6-difluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide, 7- cyclohexylamide chloro-4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f | [1,4] oxazepine-5-carboxylic acid, cyclohexylamide 7-bromo -4- (4-chloro-2-fluorobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid or cyclohexylamide 7-bromo- 4- (4-dimethylaminobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid. 5. The compound of claim 2, wherein R ³ is C ₃ -C ₇ cycloalkyl and R ⁴ is tetrahydropyran-4-yl. 6. The compound according to claim 5, which is 7-chloro-2-ethyl-3-oxo-4- (tetrahydropyran-4-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] cyclohexylamide ] oxazepine-5-carboxylic acid. 7. The compound of claim 2, wherein R ³ is cycloalkyl and R ⁴ is tetrahydronaphthalen-1-yl. 8. The compounds according to claim 7, which are the following compounds: 7-chloro-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid or 8-diethylamino-2-isopropyl-3-oxo-4- (1,2,3,4-tetrahydronaphthalen-1-yl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine- cyclohexylamide 5-carboxylic acid. 9. The compound of claim 2, wherein R ³ is C ₃ -C ₇ cycloalkyl and R ⁴ is - (CH ₂ ) _o- pyridin-3-yl. 10. The compound according to claim 9, which is a 7-chloro-2-isopropyl-3-oxo-4-pyridin-3-ylmethyl-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid cyclohexylamide. 11. The compound of claim 2, wherein R ³ is lower alkyl and R ⁴ is - (CH ₂ ) _o- phenyl substituted with a dihalo or NR′R ″ group. 12. The compounds of claim 11, which are the following compounds: 7-chloro-4- (2,6-difluorobenzyl) -2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide, 4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid, 7-chloro-4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid, 4- (4-dimethylaminobenzyl) butylamide -2-isopropyl-8-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid or 7-bromo-4- (4-dimethylaminobenzyl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide. 13. The compound according to claim 2, where R ³ represents C ₁ -C ₆ alkyl, and R ⁴ represents - (CR'R ″) oindol-3-yl substituted with C ₁ -C ₆ alkoxy. 14. The compound of claim 13, which is 9-ethoxy-2-isopropyl-4- [2- (5-methoxy-1 H-indol-3-yl) ethyl] -3-oxo-2 tert-butylamide, 3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid. 15. The compound of claim 2, wherein R ³ is C ₁ -C ₆ alkyl and R ⁴ is C ₃ -C ₇ cycloalkyl. 16. The compound according to item 13, which is a 7-chloro-4-cyclopentyl-2-ethyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid tert-butylamide. 17. The compound according to claim 2, where R ³ represents C ₁ -C ₆ alkyl and R ⁴ represents - (CH ₂ ) _o- benzo [1,3] dioxol-5-yl. 18. The compound according to 17, which is a 4-benzo [1,3] dioxol-5-ylmethyl-8-diethylamino-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepin-5- tert-butylamide carboxylic acid. 19. The compound according to claim 2, where R ³ represents C ₁ -C ₆ alkyl and R ⁴ represents 1-benzyl-piperidin-4-yl. 20. The compound according to claim 19, which is a tert-butylamide, 4- (1-benzylpiperidin-4-yl) -2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid. 21. The compound according to claim 2, where R ³ represents - (CH ₂ ) _m -feiyl, and R ⁴ represents a C ₃ -C ₇ cycloalkyl. 22. The compound according to item 21, which is a 7-chloro-4-cyclohexyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carboxylic acid benzylamide. 23. The compound according to claim 2, where R ³ represents a group - (CH ₂ ) _m -C (O) O- (C ₁ -C ₆ alkyl), and R ⁴ represents - (CH ₂ ) _o- phenyl, substituted with CF ₃ or halogen. 24. The compounds of claim 23, which are the following compounds: {[7-chloro-2-isopropyl-3-oxo-4- (3-trifluoromethylbenzyl) -2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5-carbonyl] amino tert-butyl ester } acetic acid or tert-butyl ester {[7-bromo-4- (2-chlorobenzyl) -2-isopropyl-9-methoxy-3-oxo-2,3,4,5-tetrahydrobenzo [f] [1,4] oxazepine-5 -carbonyl] amino} acetic acid. 25. A drug containing one or more compounds according to any one of claims 1 to 24 and pharmaceutically acceptable excipients. 26. The drug according to item 25 for the treatment of Alzheimer's disease. Priority on points: 05/19/2003 - paragraphs 1-26.